Asymmetric synthesis of chiral beta-amiNo acids

Abstract

The invention herein is directed to a process for the preparation of ethyl 3S-amino-4-pentynoate which involves treating 3-(trimethylsilyl)-2-propynal with L-phenylglycinol in toluene to produce αS- 3-(trimethylsilyl)-2-propynylidene amino!benzenethanol; reacting αS- 3-(trimethylsilyl)-2-propynylidene!amino!benzenethanol with BrZnCH 2 CO 2 t-Bu in THF/NMP to produce 1,1-dimethylethyl 3S- (2-hydroxy-1S-phenylethyl)amino!-5-(trimethylsilyl)-4-pentynoate; reacting the 1,1-dimethylethyl 3S- (2-hydroxy-1S-phenylethyl)amino!-5-(trimethylsilyl)-4-pentynoate with sodium periodate to form 1,1-dimethylethyl 3S- (phenylmethylene)amino!-5-(trimethylsilyl)-4-pentynoate; hydrolyzing 1,1-dimethylethyl 3S- (phenylmethylene)amino!-5-(trimethylsilyl)-4-pentynoate to produce 1,1-dimethylethyl 3S-amino-5-(trimethylsilyl)-4-pentynoate; transesterifying 1,1-dimethyl 3S-amino-5-(trimethylsilyl)-4-pentynoate and desilylating to produce ethyl 3S-amino-4-pentynoate.

What is claimed is: 
     
       1. A process for the preparation of a chiral β-amino acid of the formula ##STR49## which comprises treating 3-(trimethylsilyl)-2-propynal with L-phenylglycinol to produce αS-  3-(trimethylsilyl)-2-propynylidene!amino!benzene-ethanol; reacting αS-  3-(trimethylsilyl)-2-propynylidene!amino!benzenethanol with BrZnCH 2  CO 2  t-Bu to produce 1,1-dimethylethyl 3S- (2-hydroxy-1S-phenylethyl)amino!-5-(trimethylsilyl)-4-pentynoate; reacting 1,1-dimethylethyl 3S- (2-hydroxy-1S-phenylethyl)amino!-5-(trimethylsilyl)-4-pentynoate with sodium periodate to form 1,1-dimethylethyl 3S- (phenylmethylene)amino!-5-(trimethylsilyl)-4-pentynoate; hydrolyzing 1,1-dimethylethyl 3S- (phenylmethylene)amino!-5-(trimethylsilyl)-4-pentynoate to produce 1,1-dimethylethyl 3S-amino-5-(trimethylsilyl)-4-pentynoate; transesterifying 1,1-dimethylethyl 3S-amino-5-(trimethylsilyl)-4-pentynoate and desilylating to produce ethyl 3S-amino-4-pentynoate. 
     
     
       2. The process according to claim 1 wherein the 3-(trimethylsilyl)-2-propynal is treated with L-phenylglycinol in toluene. 
     
     
       3. The process according to claim 1 wherein the αS-  3-(trimethylsilyl)-2-propynylidene!amino!benzenethanol is reacted with BrZnCH 2  CO 2  t-Bu in THF/NMP. 
     
     
       4. The process according to claim 1 wherein the 1,1-dimethyl 3S- (2-hydroxy-1-S-phenylethyl)amino!-5-(trimethylsilyl)-4-pentynoate is reacted with sodium periodate in the presence of methylamine in ethanol/water. 
     
     
       5. The process according to claim 1 wherein 1,1-dimethylethyl 3S- (phenylmethylene)amino!-5-(trimethylsilyl)-4-pentynoate is hydrolyzed in the presence of para-toluenesulfonic acid in MTBE, THF or toluene. 
     
     
       6. A process for the preparation of an (R) β-amino acid of the formula ##STR50## wherein R is selected from the group consisting of alkynyl, alkenyl, lower alkyl, aryl, substituted aryl, pyridyl and furanyl; and R 1  is alkyl; comprising treating an aldehyde of the formula ##STR51## with (R) phenylglycinol in tetrahydrofuran or toluene to produce an imino alcohol of the formula ##STR52## reacting said imino alcohol with BrZnCH 2  CO 2  -t-Bu in NMP, DMSO, THF or NMP/THF followed by addition of acidic ammonium chloride/HCl or basic ammonium hydroxide to give an amino alcohol of the formula ##STR53## reacting said amino alcohol with NaIO 4  in the presence of methyl amine in ethanol/water or lead tetraacetate in methanol to form an imine of the formula ##STR54## and hydrolyzing said imine in the presence of para-toluenesulfonic acid to produce an (R)-amino acid of the formula ##STR55## 
     
     
       7. The process according to claim 6 wherein R is phenyl. 
     
     
       8. The process according to claim 6 wherein R is 3,5-dichlorophenyl. 
     
     
       9. The process according to claim 6 wherein R is 3-pyridinyl. 
     
     
       10. The process according to claim 6 wherein R is 2-furanyl. 
     
     
       11. The process according to claim 6 wherein R is t-butyl. 
     
     
       12. The process according to claim 6 wherein R is isopropyl. 
     
     
       13. A process for the preparation of an (S) β-amino acid of the formula ##STR56## wherein R is selected from the group consisting of alkynyl, alkenyl, lower alkyl, aryl, substituted aryl, pyridyl and furanyl; and R 1  is alkyl; comprising treating an aldehyde of the formula ##STR57## with (S) phenylglycinol in tetrahydrofuran or toluene to produce an imino alcohol of the formula ##STR58## reacting said imino alcohol with BrZnCH 2  CO 2  -t-Bu in NMP, DMSO, THF or NMP/THF followed by addition of acidic ammonium chloride/HCl or basic ammonium hydroxide to give an amino alcohol of the formula ##STR59## reacting said amino alcohol with NaIO 4  in the presence of methyl amine in ethanol/water or lead tetraacetate in methanol to form an imine of the formula ##STR60## and hydrolyzing said imine in the presence of para-toluenesulfonic acid to produce an (S)-amino acid of the formula ##STR61## 
     
     
       14. The process according to claim 13 wherein R is phenyl. 
     
     
       15. The process according to claim 13 wherein R is 3,5-dichlorophenyl. 
     
     
       16. The process according to claim 13 wherein R is 3-pyridinyl. 
     
     
       17. The process according to claim 13 wherein R is 2-furanyl. 
     
     
       18. The process according to claim 13 wherein R is t-butyl. 
     
     
       19. The process according to claim 13 wherein R is isopropyl.